Brain Regeneration

Biologists have learned how the axolotl regenerates the brain

Mikhail Orlov, Naked Science

The axolotl is an amazing animal in itself, because it is a neotenic form of the tailless amphibian ambystoma (Ambystoma mexicanum). This means that in the process of evolution, axolotls have learned to reproduce, lingering at the larval stage of development and doing without metamorphosis, which turns them into an adult.

However, the unique amphibian has another "superpower" — we are talking about its fantastic regeneration. The Axolotl costs nothing not only to heal severe wounds, but also to regrow lost limbs, tail, heart and even brain. This is also why this relative of salamanders has turned out to be a popular object of biological research.

At the same time, the axolotl gained popularity among the owners of terrariums due to its exotic appearance and very cute "expression" of the muzzle.

In a new article for the leading scientific journal Science (Wei et al., Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration), scientists describe the molecular mechanisms of axolotl regeneration, namely— its damaged brain. On this occasion, his photo even flaunts on the cover of this prestigious publication.

The very possibility of an amphibian to recreate the most complex organ is not news: biologists learned about it back in 1964. Then it was possible to show that a large axolotl is not afraid of losing a part of the brain (even a fairly large one), because it recovers quite quickly.

At the same time, biologists believed that the axolotl could not fully recreate the structure of the lost brain tissues.

This issue was addressed by the authors of a new publication — researchers from the Swiss Higher Technical School of Zurich (Switzerland) and the Institute of Molecular Pathology (Austria), who study the process of tissue regeneration at the molecular level. In this case, they were interested in whether the axolotl would be able to recreate all those different types of cells that were present in the remote part of his brain—that is, whether the new organ would be structurally complete.

The authors approached the problem thoroughly — earlier they even published an anatomical atlas of the brain of this amphibian. As a result, a lot of new things became known about the causes of its regenerative ability, and about the evolutionary past of the Ambystoma mexicanum species.

To know exactly which tissues and cells they are dealing with and to get a high-resolution picture of what is happening, biologists turned to the method of transcriptomics of single cells (single-cell RNA sequencing, scRNA-seq).

Unlike studying the morphology of neurons and even their biochemical markers, this technique is extremely accurate. Specific genes work in different cells at a certain point in time — this can be judged by RNA molecules that are analyzed using scRNA-seq.

Previously, this advanced technique was applied to fish, reptiles, mice and humans, but not amphibians — and a new publication has filled the gap.

The authors focused their attention on a certain part of the brain, the so-called terminal brain, or telencephalon. In humans and other mammals, this division includes the large hemispheres responsible for the most complex behavioral and cognitive functions.

In the process of evolution, the telencephalon has undergone strong changes — it has become much larger and more complex. However, it has a common origin in all vertebrates, therefore, studying its development on the example of the axolotl, we will also learn about the evolution of the human brain.

The authors applied transcriptomics of single cells to various cells in the terminal brain, including undifferentiated neuroblasts. They either reproduce themselves or become new neurons — in other words, thanks to them, nerve cells are successfully restored.

So, biologists have found out which genes are active in progenitor cells when they turn into neurons. It turned out that such differentiation occurs through the stage of special intermediate cells, which were not previously known. After removing a part of the axolotl's terminal brain, scientists observed its regeneration for 12 weeks and noted the appearance of new cell populations based on characteristic patterns of gene expression in them.

It turned out that the axolotl really successfully and fully restores the tissues of the damaged and even partially lost brain — for this, the amphibian has a complex and multi-stage regulation of the brain regeneration process.

At the first stage of regeneration, the number of progenitor cells increases, some of them initiate wound healing. On the second, these cells begin to differentiate into neuroblasts. At the third, final stage, neuroblasts give rise to specialized cells that exactly correspond to the original neurons — and the axolotl regains a full-fledged brain.

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